This project investigates the molecular biology of follicular lymphoma progression to identify prognostic markers and to develop a general biologic model for cancer progression. We have chosen follicular lymphoma as our primary model because it is a homogeneous disease, characterized primarily by a single molecular lesion (bcl-2 translocation) and because over 70% of these low grade lymphomas will evolve into a histologically distinct high grade lymphoma. For the past several years we have been analyzing the role of known oncogenes and tumor suppressor genes in a large series of progressed follicular lymphomas, using a combination of molecular genetic and immunohistochemical techniques. Recently, the lab has shown that p53 mutations are frequently found in progressed follicular lymphomas and have predictive value when they are detected in the indolent follicular lymphoma. In the last year, we have studied the role of the CDK inhibitors p15, p16, p18, p21, and p27 in lymphoma progression and have detected loss of heterozygosity (LOH) at chromosome 9p13, the locus of p16 in a high percentage of progressed lymphomas. In collaboration Dr. Wyndham Wilson of the Medicine Branch, DCS, NCI, we have also shown that p53 mutations in progressed high grade lymphomas predict poor response to chemotherapy. We are currently using a gene array approach to identify additional genes and gene pathways involved in follicular lymphoma progression. This approach involves laser capture microscopy (LCM) to obtain pure populations of tumor cells for the experiments. To accurately define the tumor cell populations, we developed an immunohistochemical method suitable for extraction of mRNA from LCM dissected material, and are working on a method for amplifying small amounts of cDNA representatively. In our initial experiments we will be comparing gene expression patterns obtained from mRNA extracted from microdissected low grade and progressed follicular lymphoma specimens. - Human Tissues, Fluids, Cells, etc.